The present invention is directed to devices for electrically picking up and dispensing grains in a spatially resolved manner. Specifically, this disclosure describes novel operation techniques and bead attraction electrode biasing for bead transporter chucks. The invention provides for the application of dynamic electric fields, such as those obtained using periodic pulses or other AC waveform components, to bead attraction electrodes in lieu of quasi-static electric fields that were used previously to attract grains in bead manipulating chucks. These dynamic potentials can be used not only for attracting and retaining grains, but in grain deposition sensing by measuring accumulated charge.
Electrostatic bead transporter chucks may be used to pick up, manipulate, transport, and then discharge or place grains or objects for use in creating pharmaceutical, diagnostic or chemical compositions, or in performing assays or chemical analysis.
Bead transporter chucks act as clamps to hold or retain an object or objects. Bead transporter chucks provide superior performance for manipulating grains, such as beads with diameters of 100-300 microns in chemical synthesis, such as combinatorial chemistry for solid phase synthesis, or in an assay using PCR (polymerase chain reaction) or other materials such as powders, such as can be used to deposit pharmaceuticals on a substrate.
For example, bead transporter chucks allow deposition of grains on an array in a manner that is faster and more reliable than by the use of micropipettes, which can be inefficient, tedious, and time consuming. Another application for bead transporter chucks is synthesis of pharmaceutical compositions, especially when used to combine compounds to form compositions to be packaged into administration forms for humans or animals.
Grains containing one or more active ingredients may be deposited onto well known carriers or substrates to make pharmaceutical dosage forms. Such grains may take the form, for example, of [1] a powder, such as dry micronized forms made by air jet milling processes; [2] microspheres; [3] extremely small structures, including fullerenes, chelates, or nanotubes; or [4] liposomes and fatty droplets formed from lipids or cell membranes.
The use of bead transporter chucks provides a customized and precise method for formulating drug compositions. The transporter can be used when merging adjacent substrates carrying active ingredient to form multidosage packs, in which dosage may decrease or increase from one individual unit to the next, as in hormone-based (e.g., birth control) drugs or antibiotic remedies. Using an electrostatic bead transporter chuck, dosages may be easily established or determined by the number and/or type of grains dispensed onto each pharmaceutical carrier, or by using electrical, optical, or mechanical dosage sensing. Using bead transporter chucks to place active ingredients into pharmaceutical compositions can give high repeatability and is also advantageous when the active ingredients are not compatible, such as when the active ingredient is poorly soluble with carriers, or where a formulation or carrier negatively affects the bioavailability or stability of the active ingredient.
Although emphasis is placed in this disclosure on use of electrostatic bead transporter chucks that apply electric fields for grain retention and/or release, the teachings given here can be applied to chucks that also use other phenomena, such as the use of compressed gas or vacuum, or electrically/chemically switchable adhesives, in controlling grains and/or substrates. Electrostatic or quasi-electrostatic holding mechanisms, however, are far more benign to delicate grain structures than traditional mechanical techniques, particularly when manipulating biologically active compounds where crushing, contamination, or oxidative damage must be minimized or eliminated.
The present invention can involve use of acoustic stimulation or acoustic dispensers, where acoustic energy, provided by a speaker or piezoelectric device, is used to great advantage in grain control, that is, propelling and/or tribocharging grains prior to, and especially during, electrostatic manipulation. Tribocharging grains, as known in the art, and described below, is more efficient and less damaging to the grains than corona or plasma charging, which typically requires high applied voltages of around 5 kV. Often, the sonically vibrating membrane or mesh used in such an acoustic grain dispenser can itself be used to tribocharge the particles, eliminating the need to charge the grains prior to their entry into the acoustic dispenser. The use of acoustic dispensers allows polarity discrimination of grains, where wrongly charged grains are discouraged from being retained by the bead transporter chuck. Other forms of charging and dispensing the grains can be used, such as those described in U.S. application Ser. No. 09/09/095,246, filed Jun. 10, 1998. This concurrently filed application describes grain feed systems that use augers, jet mills or fluidized beds, gas-driven Venturi, and induction charging in grain feed tubing.
Many bead transporter chucks offer precision in being able to have one, and only one grain attracted, transported, and discharged for each bead transporter chuck, or for each well, pixel, or individual spatial element of the bead transporter chuck. In many cases, each pixel can be considered a tiny bead transporter chuck that is selectively and independently controlled, such as planar chucks having individually addressable x and y coordinates. This includes individually addressable pixels for different (multiple) grain types.
Grains manipulated by these bead transporter chucks (or bead manipulating chucks) can be easily and controllably releasable, with wrongly charged grains (objects or grains having a charge of the opposite polarity desired) not occupying bead retaining or collection zones on the bead transporter chuck. They function well for a wide range of grain diameters, including grains with general dimensions of 100 microns and up, grains of much smaller dimensions, and also including porous or hollow grains that have high charge/mass ratios. They also offer durability and re-usability, and good ease-of-use, including having selectively or wholly transparent elements for easy movement and alignment of the chuck with intended targets or carriers.
Often, instead of depositing grains singly, bead transporter chucks are used to attract and place powder, such as powder containing active ingredient, on a substrate, such an edible substrate used for pharmaceutical dosage forms.
Electrodes used for attracting grains can be directly exposed, or covered by a dielectric, to prevent ionic breakdown (sparking) in air and to make use of the properties of dielectric to enhance grain holding capacity. To control the amount of charged grains that may be attracted, an indirect method can be used where an attraction electrode is not used directly to attract grainsxe2x80x94but rather is used to capacitively couple, as discussed below, to a pad or floating electrode. This floating electrode then develops image charges partly in response to the field generated by the bead electrode, and its operation is self limiting in that it can only serve to attract a finite amount of charge before the potential it generates is cancelled. This indirect charging method can be more gentle, more precise, and less expensive to implement than charging by corona discharge, particularly for high resolution applications. The instant invention can be applied to any number of bead transporter chuck designs, but for illustration purposes, the chuck shown here attracts grains indirectly by way of one or more floating electrodes. Other useful electrode designs are illustrated in U.S. application Ser. No. 09/095,246, filed Jun. 10, 1998. Further techniques employed for precise dosage control include the use of sensing electrodes used for grain deposition sensing. Sensing electrodes can be thought of as equivalent to bead transporter chucks dedicated to, and specially monitored for accumulated grain charge.
However, bead transporter chuck designs and operation techniques that use simple static or quasi-static direct current (DC) potentials applied to attraction electrodes to pick up and discharge grains can, under certain conditions, encounter serious problems with grain attraction and charge control.
One problem encountered is the conductivity of resistive substrates does not allow for charge retention needed for attracting grains or powder to the substrates. Previous chucks were designed initially for use with quasi-static DC bias conditions, with selective application of DC potentials to bead attraction electrodes for grain pickup. Generally, polarities were reversed to aid in grain discharge only. These chucks using quasi-static grain attraction voltages were well suited for grains (e.g., powders) and substrates possessing high resistivity, such as insulators or polymeric films having a bulk resistivity xcfx81 on the order of about 1015 xcexa9-cm.
Unfortunately, many bead transporter chucks using quasi-static DC potentials applied to grain attracting electrodes are simply not responsive or effective for lower resistivity grains or substrates. Because of the higher conductivity of low resistivity grains or substrates, DC or quasi-staticly generated charges within the grain or substrate decay rapidly using higher conductivity substrates or grain compositions. This rapid decay or leakage of charge comes about through internal movement of charges within the grain or substrate and by stray leakage, often aided by ambient humidity. This makes the bead transporter chuck useless in attracting and retaining higher conductivity grains or powders. In using, for example, a bead transporter chuck employing capacitive coupling to a floating electrode, there is only a finite amount of charge-inducing and attraction capacity available. With lower resistivity beads or substrates, the induced-charge gathering potential on areas adjacent to the floating pad, such as on a substrate, can decay to zero in a matter of a few millisecondsxe2x80x94and this is usually not enough time to accelerate, transport, and retain grains in intended bead collection zones.
Specifically, this invention addresses problems encountered with substrates having insufficient resistivity xcfx81, such as substrates having bulk resistivities ≯of 1010 or 1011 xcexa9-cm. As discussed below, the circuit elements in many bead transporter chucks have electrical properties that are characteristic of RC circuits (circuits having significant resistance and capacitance elements), and the charge Q used for grain attraction that remains from an initial amount of attraction charge Q0 on a grain or substrate as a function of time can be described by an exponential function
Q=Q0e(xe2x88x92kt)xe2x80x83xe2x80x83(1)
having a characteristic time constant k equal to the overall resistance R times the overall capacitance C:
k=RCxe2x80x83xe2x80x83(2)
This time constant k is known as an xe2x80x9cRCxe2x80x9d time constant, and when R and C are expressed in SI units, it has units of seconds. The resistance R is derived from the resistivity by taking into account the cross-sectional area A and length l of the material in question:
R=(xcfx81l)/Axe2x80x83xe2x80x83(3)
where xcfx81 is the bulk resistivity or the equivalent, expressed in standard SI units of ohm-meters.
With prior bead transporter chucks and operation techniques, the resistivity xcfx81 often has to be in excess of 1.1xc3x971011 xcexa9-cm in order to have a time constantxe2x80x94that is, a time in which most grain attraction and deposition must occur (see definition below)xe2x80x94on the order of seconds or more. This problem is particularly acute when dealing with certain edible substrates, such as polyvinylacetate or hydroxypropylmethylcellulose which can have bulk or equivalent surface resistivities xcfx81 well below 1011 xcexa9-cm, where the resultant time constant is on the order of tens of milliseconds, which is usually not enough time to accelerate, transport, attract and retain beads.
The result of such low time constants is that because of the internal charge movement and leakage, fewer grains than desired, or no grains, are attracted to intended bead collection zones and/or substrates during bead transporter chuck operation. During synthesis or analysis, instead of retaining a precise amount of ingredients carried by graiss into each bead collection zone or substrate, little or no grain content is attracted and retained where desired, when using quasi-static attracting voltages needed for efficient manipulation of the grains.
In seeking to avoid this lack of chuck response by greatly increasing the applied (attraction) voltage, the attraction field can then be then too strong, causing grains to be attracted to unintended or wrong locations on the bead transporter chuck, or wrongly charged grains to be attracted to the bead transporter chuck or substrate. The same problem also makes it difficult or impossible to perform accumulated charge sensing to gauge how much active ingredient has been attracted and retained by the bead transporter chuck.
It is important to note that many electrostatic bead transporter chucks manipulate charged grains by making use of electrostatic image forces. As a charged grain approaches any metal or conductive surface, such as a bead attraction electrode inside the grain dispenser or container, an image charge of opposite polarity will accumulate on that conductive surface. This happens when mobile charge carriers in the conductive surface are attracted by, or repelled by, the grain charge. This movement of charge in the conductive surface in response to a charged grain in the vicinity creates a potent image charge-induced holding force, or electrostatic image force. This electrostatic image force tends to make the grain highly attracted to, and usually later, in tight contact with, the conductive surface. It should be noted that dielectric grains in stationary tight contact with a conductive surface have a tendency to keep their charge for a period of days. With a grain very close to (e.g., contacting) any conductor, the electrostatic image force generated tends to be greater than that due to any applied field used to accelerate the grains toward the bead transporter chuck, and can be on the order of hundreds of times the force due to gravity.
Typically grains to be transported or manipulated are tribo-charged through frictional encounters and collisions, such as rubbing or bumping into surfaces, where charging can occur by charge induction or charge transfer. The particular charge transfer mechanisms used in a tribo-charging process will determine the applied voltages that should be used on a tribo-charging mesh.
Also, grain motions and interactions, or collisions with obstaclesxe2x80x94and each otherxe2x80x94inside a dispenser or container tend to randomize their motion, and this influences grain transport properties, as grains are accelerated toward intended bead collection zones.
As discussed below, another problem present in quasi-static biasing techniques involves grain deposition sensing, where an accumulated charge sensing method is used. The static nature of the applied potentials used to attract charged grains to the sensing electrode introduces opportunities for various types of noisexe2x80x94such as shot noise, Johnson (1/f) noise, thermal noise, Galvanic noise, and amplifier noisexe2x80x94to destroy the accumulated charge sense information sought for effective and precise grain accumulation or powder deposition monitoring.
Methods for use of bead transporter chucks and acoustic grain dispensers are set forth in Pletcher et al., xe2x80x9cApparatus for electrostatically depositing a medicament powder upon predefined regions of a subsrate,xe2x80x9d U.S. Pat No. 5,714,007, issued Feb. 3, 1998; Pletcher et al., xe2x80x9cMethod and apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate,xe2x80x9d U.S. Pat. No. 6,007,630issued Dec. 28, 1999; Pletcher et al; xe2x80x9cMethod and apparatus for eletrostatically depositing a medicament powder upon predefined regions of a substrate,xe2x80x9d U.S. Pat. No. 6,074,688, issued Jun. 13, 2000; Pletcher, xe2x80x9cApparatus for electrostatically depositing and retaining materials upon a substrate,xe2x80x9d U.S. Pat. No. 5,669,973, issued Sep. 23, 1997; Datta et al., xe2x80x9cInhaler apparatus with modified surfaces for enhanced release of dry powders,xe2x80x9d U.S. Pat. No. 5,871,010, issued Feb. 16, 1999; Sun st al., xe2x80x9cAcoustic dispenser,xe2x80x9d U.S. Pat. No. 5,753,302, issued May 19, 1998; Sun et al., xe2x80x9cMethod of Making Pharamaceutical Using Electrostatic Chuck,xe2x80x9d U.S. Pat. No. 5,846,595, issued Dec. 8, 1998; Sun et al., xe2x80x9cElectrostatic Chucks,xe2x80x9d U.S. Pat. No. 5,858,099, issued Jan. 12, 1999; Sun, xe2x80x9cChucks and Methods for Positioning Multiple Objects on a Substrate,xe2x80x9d U.S. Pat. No. 5,788,814issued Aug. 4, 1998; Loewy et al., xe2x80x9dDeposited Reagents for Chemical Processes,xe2x80x9d U.S Pat. Np. 6.095,753, issued Apr. 4, 2000; Loewy et al., xe2x80x9cSolid Support With Attached Molecules,xe2x80x9d U.S. Pat. No. 6,004,752, issued Dec. 21, 1999; Sun, xe2x80x9cBead Transporter Chucks Using Repulsive Field Guidance,xe2x80x9d U.S. Pat. No. 6,096,368, issued Aug. 1, 2000; Sun, xe2x80x9dBead manipulating Chucks with Bead Size Selector,xe2x80x9d, U.S. pat. No. 5,988,432, issued Nov. 23, 1999; Sun, xe2x80x9cFocused Acoustic Bead Charger/Dispenser for Bead Manipulating Chucks,xe2x80x9d U.S. Pat. No. 6,168,666, issued Jan. 2, 2000. Additional instructional information is found in Poliniak et at., xe2x80x9cDry Powder Deposition Apparatus,xe2x80x9d U.S. application U.S. Pat. No. 6,063,194, issued May 16, 2000; Sun et al., xe2x80x9cApparatus for Clamping a Planar Substrate,xe2x80x9d U.S. application Ser. No. 09/095,321, filed Jun. 10, 1998, now U.S. Pat. No. 6,399,163; and xe2x80x9cPharamaceutical Product and Method of Making,xe2x80x9d U.S. Pat. No. 6,303,143, issued Oct. 16, 2001.
It is therefore desirable to lower the resistivity or charge retention requirement for eligible substrates, allowing for acceleration and attraction of grains to intended bead collection zones or substrates using grains or substrates that are otherwise not workable, as discussed above. Preferably, this should be done while providing grain deposition in a preferred direction and location in conjunction with electrostatic image forces.
Moreover, it is also desirable to have a means for dose monitoring, or grain deposition monitoring. This should allow for accumulated charge sensing with precision in knowing how much charge accumulates on individual substrates or at bead collection zones. Specifically, it is desirable to be able to perform accumulated charge sensing while the bead transporter chuck is in operation, in an effective manner, overcoming the deleterious effects of various noise sources that plague quasi-static biasing techniques.
In attracting and manipulating grains, image charges, electric polarization, and grain mass and transport, play a role.
These problems are addressed by this invention by introducing AC waveform biasing to attract grains on a bead contact surface of a bead transporter chuck. The beads are directed to bead collection zones on the bead contact surface using pulses or other dynamic, non-static bead electrode bias waveforms which may included AC and DC components, and do not have to be periodic.
In one embodiment, a bead transporter chuck using AC waveform biasing for attracting grains to a bead collection zone on a bead contact surface, and for retaining and discharging grains from the bead collection zone, comprises a bead electrode for selectively establishing a grain attracting field to the bead collection zone, with the bead electrode shaped and configured in such a manner so that when an AC waveform potential is applied to it, the grains are influenced by it and guided to selective retention by the bead electrode to the bead collection zone.
The bead transporter chuck can optionally comprise a dielectric positioned between the bead electrode and the bead contact surface. It can also optionally comprise a shield electrode positioned to shape the attractive field initiated by the bead electrode, and/or it can comprise a floating pad electrode, which in one embodiment is positioned between the dielectric and the bead contact surface. The shield electrode can be shaped and configured so as to allow an electric field from the bead electrode to emanate through the bead collection zone. The shield electrode can be, for example, positioned between the dielectric and the bead contact surface, and formed and configured as to surround, but remain electrically isolated from, the floating pad electrode. If desired, a second dielectric may be positioned between the shield electrode and the bead contact surface or between the floating pad electrode and the bead contact surface, or both.
The bead transporter chuck can comprise a charge collector electrode or a coupling capacitor, or both, for monitoring accumulated charge on the bead collection zone of the bead contact surface.
The AC waveform potential used by the bead transporter chuck can be so chosen and configured so as to provide for a repeated attraction potential at the bead collection zone of the bead contact surface, when the bead collection zone is proximate to a material, such as a low resistivity substrate, that has an RC decay of a charge on the material when the repeated attraction potential is applied. The AC waveform potential is configured such that the time average of the grain attraction potential on the bead collection zone whenever the grain attraction potential acts is greater, on average, than that a second grain attraction potential that would be obtained when applying an equivalent time-averaged DC potential corresponding to the AC waveform potential.
The AC waveform potential can also be chosen so as to maximize a grain attraction potential at the bead collection zone of the bead contact surface, wherein an integral of the absolute value of VBCZ with respect to time, between a point A and a point B on the AC waveform,                                           ∫            A            B                    "RightBracketingBar"                ⁢                  V          BCZ                ⁢                  "LeftBracketingBar"                      xe2x80x83                    ⁢                      ⅆ            t                                              (        4        )            
is maximized, with the value of the integral being greater than obtained using a second AC waveform potential not so optimized.
The invention also provides for an accumulated charge sensing circuit for a bead transporter chuck having a charge sensing electrode for monitoring accumulated charge on the bead collection zone of the bead contact surface. This charge sensing circuit comprises a sensing capacitor electrically connected between the charge collector electrode and an AC bias source; and an electrometer electrically connected between the AC bias source and the coupling capacitor so as to be able to measure the potential of the sensing capacitor. The accumulated charge sensing circuit can be used in a process to determine when to stop grain accumulation or to monitor accumulation at various regions on a bead transporting chuck so that process adjustments, such as changes in grain-attracting potentials, can be made on-the-fly.
Another embodiment for an accumulated charge sensing circuit comprises a transformer having a primary winding and a secondary winding, the primary and secondary windings each having first and second poles; the charge collector electrode electrically connected to the first pole [BP] of the secondary winding of the transformer; a sensing capacitor connected between a ground and the second pole [CP] of the secondary winding of the transformer; an electrometer electrically connected between the second pole [CP] of the secondary winding of the transformer and the ground; and an AC bias source connected across the first and second poles of the primary winding of the transformer.
Methods are disclosed for using a bead transporter chuck using an AC bias waveform, with steps including some or all of the following:
[a] applying a first potential to the bead electrode of the bead transporter chuck to create a grain attracting field; and
[b] attracting and retaining a grain to the bead collection zone;
[c] reducing the first potential applied to the bead electrode, thereby reducing the grain attracting field sufficiently so as to discharge a grain from the bead collection zone to a desired location;
[d] aligning the bead transporter chuck with the desired location prior to step [c];
[e] using a bead transporter chuck that comprises a shield electrode positioned between the bead electrode and the bead contact surface; the shield electrode shaped and configured to allow beads to be influenced by the bead electrode;
[f] grounding the shield electrode;
[g] applying a second potential of opposite polarity to the first potential of step [a] to the shield electrode during grain discharge.